Black Death linked to evolution of immune system genes and autoimmune diseases

Genetic variants that helped people survive the Black Death could today increase the risk of autoimmune diseases, researchers report.

In the 14th century, the Black Death (also known as bubonic plague) killed up to 50 percent of people living in Europe, Africa, and the Middle East, in the worst-known pandemic in human history. Changes in hygiene and sanitation are often credited for helping control the disease caused by the Yersinia pestis flea-borne bacterium. But researchers studying DNA from skeletons buried at the time have discovered that certain genetic variants could also have helped people to survive, and those variants remain common today.

'This is, to my knowledge, the first demonstration that indeed, the Black Death was an important selective pressure to the evolution of the human immune system,' said co-senior author of the study, Professor Luis Barreiro from the University of Chicago.

Publishing their research in Nature, the researchers used the latest technology in ancient DNA analysis to read DNA sequences from around 500 skeletons buried in London and Denmark around the time of the 1346-1350 plague pandemic.

Focusing on immunity-related genes, they found sequence variations that were more common in survivors than people who died from the disease or died before the pandemic started. They suggest these variants could have helped with survival, which is what caused them to become more common in the population.

The researchers zeroed in on one variant of the gene ERAP2, which had a particularly strong association with survival. This 'advantageous' variant produces a full-length functional ERAP2 protein which helps the immune system recognise the presence of an infection. Another 'dysfunctional' variant of ERAP2 shortens the protein and prevents it from working. The researchers estimate that carrying two copies of the 'advantageous' variant would make a person 40 percent more likely to survive the Black Death.

The team tested the idea that ERAP2 is protective against the Black Death by exposing isolated human cells with or without the 'advantageous' ERAP2 variant to the disease-causing Y. pestis bacterium. Functional ERAP2 stimulated a protective immune response, controlling the Y. pestis bacteria and reducing cell death more than in cells without it.

However, the researchers conclude that though the ERAP2 variant protects against the Black Death, it is known to carry an increased risk of developing autoimmune diseases, such as Crohn's disease. Another variant found under positive selection in this study increased the risk of developing rheumatoid arthritis.

'These genes are under balancing selection – what provided tremendous protection during hundreds of years of plague epidemics has turned out to be autoimmune related now,' said Professor Hendrik Poinar from McMaster University, Canada, co-senior author of the study. 'A hyperactive immune system may have been great in the past but in the environment today it might not be as helpful.'